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Anthracycline-based chemotherapy has been mainstay of adjuvant breast cancer therapy for decades. Although effective, anthracyclines place long-term breast cancer survivors at risk of late effects, such as reduced cardiorespiratory fitness and increased risk of cardiovascular disease. Previous research has shown beneficial effects of exercise training on cardiorespiratory fitness, but the effects of exercise on limiting factors for cardiorespiratory fitness, cardiovascular risk factors, and patient-reported outcomes in long-term survivors are less clear. Whether previous exposure to breast cancer therapy modulates the effects of exercise is also unknown.
The primary aim of the CAUSE (Cardiovascular Survivors Exercise) trial is to examine the effect of aerobic exercise on cardiorespiratory fitness in anthracycline-treated long-term breast cancer survivors. Secondary aims are to examine effects of exercise training on limiting factors for cardiorespiratory fitness, cardiovascular risk factors, and patient-reported outcomes, and to compare baseline values and effects of exercise training between similar-aged women with and those without prior breast cancer. A third aim is to examine the 24-month postintervention effects of aerobic exercise on primary and secondary outcomes.
The CAUSE trial is a 2-armed randomized controlled trial, where 140 long-term breast cancer survivors, 8-12 years post diagnosis, are assigned to a 5-month nonlinear aerobic exercise program with 3 weekly sessions or to standard care. Seventy similar-aged women with no history of cancer will undergo the same exercise program. Cardiorespiratory fitness measured as peak oxygen consumption (VO2peak), limiting factors for VO2peak (eg, cardiac function, pulmonary function, hemoglobin mass, blood volume, and skeletal muscle characteristics), cardiovascular risk factors (eg, hypertension, diabetes, dyslipidemia, obesity, physical activity level, and smoking status), and patient-reported outcomes (eg, body image, fatigue, mental health, and health-related quality of life) will be assessed at baseline, post intervention, and 24 months post intervention.
A total of 209 patients were included from October 2020 to August 2022, and postintervention assessments were completed in January 2023. The 24-month follow-up will be completed in February 2025.
The findings from the CAUSE trial will provide novel scientific understanding of the potential benefits of exercise training in long-term breast cancer survivors.
ClinicalTrials.gov NCT04307407; https://clinicaltrials.gov/ct2/show/NCT04307407
DERR1-10.2196/45244
Due to advances in diagnostics and treatment, the 5-year survival rate for early breast cancer has surpassed 90% in the Western world, and the number of breast cancer survivors (BCSs) is steadily increasing. Long-term BCS (ie, living beyond 5 years after diagnosis) are at increased risk of several late effects, such as increased risk of cardiovascular disease (CVD) and incidence cardiovascular (CV) risk factors (eg, obesity, hypertension, and dyslipidemia) [
Cardiotoxicity is a well-recognized adverse effect of anthracycline therapy, which has been a key component of breast cancer therapy for decades. Anthracycline treatment can induce myocardial damage [
Previous studies have demonstrated impaired cardiorespiratory fitness (CRF) in BCSs [
BCS may also face psychosocial late effects, including body image concerns, increased levels of mental distress [
Aerobic exercise has shown to improve CRF in cancer survivors [
In nononcological settings, higher levels of physical activity are associated with a dramatic reduction in CVD risk [
The primary aim of this study is to examine the effect of aerobic exercise on CRF in anthracycline-treated long-term BCS compared to standard care. Secondary aims are to examine the effects of exercise training on limiting factors for CRF, CV risk factors, and health-related patient-reported outcomes (PROMs) compared to standard care, and to compare baseline values and effects of exercise training between BCS and similar-aged women without prior cancer. Tertiary aims are to investigate long-term effects of the intervention on CRF, CV risk factors, and health-related outcomes 24 months post intervention. We hypothesize that aerobic exercise will improve CRF.
The CAUSE (Cardiovascular Survivors Exercise) trial is conducted according to the Helsinki Declaration, and all study participants will sign informed consent before any study-related procedures. The study is approved by the Regional Committees for Medical and Health Research Ethics (2019/1318) and is preregistered on clinicaltrials.gov (NCT04307407).
The CAUSE trial is a 2-armed, phase II randomized controlled trial that compares aerobic exercise (exercise group) to standard care (control group) in BCS. A third group comprising similar-aged women with no previous cancer diagnosis is also included (noncancer reference group). The exercise group and the noncancer reference group undergoes the same aerobic exercise program. The overall study design is outlined in
Study outline. Participants in the exercise group, control group, and noncancer reference group undergoes assessments at baseline (T1), after 5 months (post intervention) (T2), and 1 and 2 years post intervention (T3 and T4).
BCS are invited to participate if diagnosed with human epidermal growth factor receptor 2
–negative breast cancer stage I-III between 2008 and 2012 (ie, 8-14 years after diagnosis), aged 60 years or younger at the time of diagnosis, and received the anthracycline epirubicin as part of their adjuvant therapy. All eligibility criteria are listed in
Inclusion criteria:
Adjuvant treatment with epirubicin
Breast cancer diagnosis between 2008 and 2012
Exercises ≤90 minutes per week
Physicians’ approval of participation
Exclusion criteria:
Stage IV breast cancer at diagnosis
Treatment with trastuzumab
Recurrence of breast cancer
Presence of other malignancies (except for basal cell carcinomas)
Former major cardiac surgery
Presence of a pacemaker
Chronic atrial fibrillation
Recent or uncontrolled cardiovascular disease
Any physical or mental condition restricting adherence to study procedures (by self-evaluation)
Participants in the noncancer reference group are women without a history of cancer who otherwise meet the eligibility criteria listed in
Women who were diagnosed with breast cancer stage I-III between 2008 and 2012, and live within reasonable distance from Oslo, are identified from the Cancer Registry of Norway. An invitation with study information is sent by mail to all candidates. Thereafter, the study personnel contact the candidates by phone to screen for eligibility and provide additional information. Candidates who meet the eligibility criteria and are willing to participate are then invited to baseline assessments.
Participants for the noncancer reference group are recruited in 2 steps. First, BCS randomized to the exercise group are encouraged to invite a similar-aged friend or relative to participate in the noncancer reference group. The remaining participants in the noncancer reference group are recruited through advertisements in news media and through appropriate social media channels. Interested candidates who meet the eligibility criteria are included.
BCS are block randomized with a 1:1 allocation ratio to the exercise group or to the control group. Due to the strict eligibility criteria, no additional stratification factors are included. A random sequence of study IDs was made by a random number generator prior to inclusion of the first participant. The allocation sequence is concealed from the study personnel involved in baseline assessment until the baseline assessments are completed.
Study outcomes, assessment methods, and assessment times are summarized in
All participants are screened by a cardiologist before the assessments. Presence of possible contraindications to exercise training will be evaluated according to the guidelines from the American College of Sports Medicine. [
Outcomes, assessments, and time point of assessments in the CAUSE (Cardiovascular Survivors Exercise) trial.
Domain and outcomes | Assessment method | Time point of assessment | |||
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Peak oxygen consumption | Treadmill cardiopulmonary exercise test | T1, T2, T4 | ||
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Cardiac dimensions | Echocardiography | T1, T2, T4 | ||
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LVa and RVb systolic function | Echocardiography | T1, T2, T4 |
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LV diastolic function | Echocardiography | T1, T2, T4 |
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NT-proBNPc | Blood sample | T1, T2, T4 |
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Hemoglobin mass | Carbon monoxide rebreathing method | T1, T2, T4 |
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Hemoglobin concentration and blood volume | Venous blood sample and carbon monoxide rebreathing method |
T1, T2, T4 |
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Fiber size | Immunohistochemistry | T1, T2, T4 |
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Fiber composition | Immunohistochemistry | T1, T2, T4 |
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Capillaries per fiber | Immunohistochemistry | T1, T2, T4 |
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Mitochondrial proteins | Western blotting | T1, T2, T4 |
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Proteins involved in β-oxidation | Western blotting | T1, T2, T4 |
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Gene expression | Methylome wide arrays | T1, T2, T4 |
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Forced vital capacity | Spirometry | T1, T2, T4 |
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Forced expiratory volume in 1 second | Spirometry | T1, T2, T4 |
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Ventilatory capacity | Estimated from FEV1d x 40 or MVVe | T1, T2, T4 |
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DLcof for carbon monoxide | DLco test | T1, T2, T4 |
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DLco/alveolar volume | DLco test | T1, T2, T4 |
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Total Lung Capacity-SB | DLco test | T1, T2, T4 |
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Blood pressure | Electronic sphygmomanometer | T1, T2, T4 |
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Fasted glucose, HbA1cg, insulin | Blood sample | T1, T2, T4 |
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Lipids | Blood sample | T1, T2, T4 |
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High-sensitivity C-reactive protein | Blood sample | T1, T2, T4 |
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BMI | Scale and stadiometer | T1, T2, T4 |
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Lean body mass | Dual x-ray absorptiometry | T1, T2, T4 |
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Fat body mass | Dual x-ray absorptiometry | T1, T2, T4 |
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Level of physical activity | ActiGraph GT3X+ | T1, T2, T4 |
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Smoking status | HUNT-4h | T1, T2, T4 |
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Physical activity and Exercise training | HUNT-4 and GLTEQi [ |
T1, T2, T4 |
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Diet | HUNT-4 | T1, T2, T3, T4 |
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Sleep habits | Modified HUNT-4 | T1, T2, T4j |
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Work aspects | WAIk | T1, T2, T4 |
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Comorbidity | Modified HUNT-4 | T1, T2, T4 |
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HRQoLm | EORTCn QLQo-C30 [ |
T1, T2, T4 |
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QoL and Vitality | SWLSp [ |
T1, T2, T4 |
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Breast cancer–specific symptoms and complaintsr | EORTC QLQ-BR23 [ |
T1, T2, T4 |
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Neuropathy | SCINs [ |
T1, T2, T4 |
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Fatigue | Chalder FQt [ |
T1, T2, T4 |
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Anxiety |
GADu7 [ |
T1, T2, T4 |
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Fear of recurrence | ASCw [ |
T1, T2, T3, T4 |
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Training motivation | BREQx 2 [ |
T1, T2, T4j |
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Exercise competence | PCSy [ |
T1, T2, T4 |
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Training need satisfactionz | BPNESaa [ |
T1, T2, T4j |
aLV: left ventricular.
bRV: right ventricular.
cNT-proBNP: N-terminal fragment of brain natriuretic peptide.
dFEV1: forced expiratory volume in 1 second.
eMVV: maximal voluntary ventilation.
fDLco: diffusion capacity of the lung for carbon monoxide.
gHbA1c: glycated hemoglobin.
hHUNT-4: The Trøndelag Health.
iGLTEQ: Godin leisure time exercise questionnaire.
j4 and 12 weeks post T1.
kWAI: Work Ability Index.
lQoL: quality of life.
mHRQoL: health-related quality of life.
nEORTC: European Organization for Research and Treatment of Cancer.
oQLQ: quality of life questionnaire.
pSWLS: satisfaction with life scale.
qSVS: subjective vitality scale.
rBody image, sexuality, lymphoedema, and pain.
sSCIN: scale for chemotherapy-induced long-term neurotoxicity.
tFQ: fatigue questionnaire.
uGAD: generalized anxiety disorder.
vPHQ: patient health questionnaire.
wASC: assessment of survivors concerns.
xBREQ-2: Behavioral Regulation in Exercise Questionnaire-2.
yPCS: perceived competence scale.
zExercise groups only.
aaBPNES: Basic Need Satisfaction in Exercise Scale.
VO2peak is assessed by an incremental treadmill cardiopulmonary exercise test (CPET) using a modified Balke protocol (RL2700E, Rodby) [
The following limiting factors for CRF were will be considered:
Cardiac function: cardiac morphology and function will be assessed by resting transthoracic echocardiography using Vivid E9 (GE Vingmed). Standard 2D parasternal and apical views are acquired in the end-expiratory phase with participants in the supine left lateral position. Apical 3D recordings will be obtained by stitching together minimum 4 consecutive heart cycles. In addition, left ventricular outflow tract velocity time integral will be obtained immediately after the CPET to estimate maximal stroke volume and cardiac output. Images will be subsequently analyzed offline on EchoPac version 202 (GE Vingmed). Echocardiographic outcomes (listed in
Pulmonary function: ventilatory function will be assessed by maximal expiratory flow volume loops (MasterScreen Pneumo Jäger) [
Blood oxygen transport capacity: hemoglobin mass will be measured using a carbon monoxide (CO) rebreathing method [
Skeletal muscle characteristics: muscle biopsies will be obtained from vastus lateralis muscle by the Bergström Needle-biopsy technique according to standard procedures established in our laboratory [
Resting blood pressure will be measured by an electronic sphygmomanometer (Welch Allyn ProBP 2400) in supine position after echocardiography. Biomarkers listed in
An overview of the PROMs is presented in
Motivation for exercise will be measured by the Behavioral Regulation in Exercise Questionnaire-2 [
The intervention duration is 5 months. Participants in the exercise group perform 3 weekly aerobic exercise sessions aimed at increasing CRF. The exercise plan includes both continuous sessions, with low to moderate exercise intensities, as well as interval sessions performed at higher intensities. The intensity and duration of each individual session and sequencing of the different sessions are outlined in
Exercise prescription outline. Bars represents the exercise intensity (% of peak heart rate) at a given exercise session, and the dotted line represents the duration (minutes) at the prescribed exercise intensity in a given session.
In
All exercise sessions will be supervised by an instructor at the participant’s local gym. The instructors make sure that the planned exercise sessions are performed and adjust the sessions if necessary. They will also register any deviation from the exercise prescription and report the reason for any adjustment following metrics suggested by Nilsen et al [
BCS randomized to the control group will be encouraged to maintain their current activity level at the time of randomization.
The sample size calculation was based on the primary outcome VO2peak, using a mean change of 3.6 (SD 7.2) mL/kg/minute, from a comparable intervention by Adams et al [
The inclusion started in October 2020 and was completed in August 2022. A total of 209 participants were included and postintervention assessments (T2) were completed in January 2023. The 24-month follow-up (T4) will be completed in February 2025.
Exercise training has previously been shown to improve CRF [
As with CRF, the positive effects of exercise training on several PROMs have been reported previously, but the existing literature is mainly limited to effects of exercise training during or shortly after cancer treatment. This is concerning, since approximately 30% of BCS still report chronic fatigue up to 10 years after completing treatment. Results from exercise training performed during or immediately after cancer treatment cannot necessarily be extrapolated to long-term survivors as the mechanisms behind chronic fatigue might differ from the more acute complaints. Although positive effects of exercise training on quality of life already have been demonstrated, less is known about the impact of exercise on other late effects in long-term BCS, such as mental distress, disturbed body image, pain, and sexual health challenges.
One of the major strengths of this study is the solid multidisciplinary constellation of the research group. Our group includes sports physiologists, cardiologists, oncologists, and behavioral scientists. This is also reflected by the list of study outcomes (
Our study design has some potential limitations. As with any lifestyle intervention study, we risk recruiting the most motivated and physically active participants, which may compromise the external validity of our results. We aim to reduce this risk of selection bias by recruiting BCS through the Cancer Registry of Norway rather than through media advertisements. Importantly, we use similar exclusion criteria for physical activity levels between cancer survivors and the reference groups, which enable us to identify any modifying effects of previous cancer treatment. Unfortunately, this study lacks completely blinded assessors. As an effort to reduce the influence of known group allocation, assessors will not know the baseline values of participants prior to the postintervention CPET. Furthermore, study staff will use similar feedback and encouragement during all tests. As in all clinical trials, poor intervention adherence and dropouts are major concerns. We attempt to counteract this by using instructors trained in motivational feedback. The knowledge acquired from this study will help to inform future cancer care guidelines.
Peer review report from the Norwegian Cancer Society's Krafttak mot kreft 2018 / Norwegian Cancer Society.
breast cancer survivor
Cardiovascular Survivors Exercise
carbon monoxide
cardiopulmonary exercise test
cardiorespiratory fitness
cardiovascular
cardiovascular disease
diffusion capacity of the lung for carbon monoxide
peak heart rate
health-related quality of life
The Trøndelag Health
health-related patient-reported outcome
peak oxygen consumption
The study is funded by the Norwegian Cancer Society and Aktiv mot kreft (Active Against Cancer). All authors were actively involved in the drafting
The data sets generated during and analyzed during the current study are available from the corresponding author on reasonable request.
None declared.